A decades long search for conclusive evidence of interplay between genotype and environment to yield a behavioral effect has not succeeded. It has long been postulated that such interplay will exist, but these have not been demonstrated prior to the invention described herein. See Rutter, M. and J. Silberg, “Gene-Environment Interplay in Relation to Emotional and Behavioral Disturbance,” Ann. Rev. Psychol. 53:463-490 (2002). Demonstration of such an effect would be of great interest to psychiatrists, psychologists, social workers, law enforcement and justice administration personnel, and others involved with behavioral issues.
The invention described in this application relates, in part, to an interaction between a pathogenic environmental risk factor (childhood maltreatment) and a genotype (allelic profile at a genetic locus that encodes monoamine oxidase A, [MAOA]). Childhood maltreatment is a universal risk factor for antisocial behavior. Boys who experience abuse—and more generally, those exposed to erratic, coercive, and punitive parenting—are at risk of developing conduct disorder, evidencing antisocial personality symptoms, and of becoming violent offenders. The earlier children experience maltreatment, the more likely they are to develop these problems. But there are large differences among children in their response to maltreatment. Although maltreatment increases the risk of later criminality by about 50%, most maltreated children do not become delinquents or adult criminals. The reason for this variability in response is largely unknown, but it may be that vulnerability to adversities is conditional upon genetic susceptibility factors.
The MAOA gene, located on the X chromosome (Xp11.23-11.4), encodes the MAOA enzyme, which metabolizes, and renders inactive, neurotransmitters such as norepinephrine (NE), serotonin (5-HT) and dopamine (DA). Genetic deficiencies in MAOA activity have been linked with aggression in mouse and man. Increased aggression, and increased levels of brain NE, 5-HT, and DA, were observed in a transgenic mouse line in which the gene encoding MAOA was deleted, and aggression was normalized by restoring MAOA expression. In humans, a null allele at the MAOA locus was linked with male antisocial behavior in a Dutch kindred. Because MAOA is an X-linked gene, affected males with a single copy produced no MAOA enzyme—effectively, a human knockout. However, this mutation is extremely rare. Evidence for an association between MAOA and aggressive behavior in the human general population remains inconclusive.
Animal studies document that maltreatment stress (e.g., maternal deprivation, peer rearing) in early life alters NE, 5-HT, and DA neurotransmitter systems in ways that can persist into adulthood and influence aggressive behaviors. In humans, altered NE and 5-HT activity are linked to aggressive behavior. Maltreatment has lasting neurochemical correlates in human children. Deficient MAOA activity may dispose the organism toward neural hyper-reactivity to threat, as evidenced by the inhibitory action of phenelzine injections which inhibit the action of monoamine oxidase and prevented rats from habituating to chronic stress. Low MAOA activity may be particularly problematic early in life, because there is insufficient MAOB (a homolog of MAOA with broad specificity to neurotransmitter amines) to compensate for an MAOA deficiency.